By Dara Jamieson, MD

Associate Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Jamieson reports no financial relationships relevant to this field of study.

SYNOPSIS: Blockade of calcitonin gene-related peptide in patients with chronic or episodic migraine results in the prevention of about two headache days a month compared to placebo.

SOURCES: Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017;377:2113-2122.

Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med 2017;377:2123-2132.

Two papers, published simultaneously in The New England Journal of Medicine, evaluated two randomized, double-blind, placebo-controlled, parallel-group, industry-funded trials of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) in the prevention of chronic or episodic migraine, using the molecule antagonist fremanezumab or the receptor antagonist erenumab, respectively.

In the paper by Silberstein et al, the two active fremanezumab treatment arms were either a one-time set of three injections of 225 mg per 1.5 mL at baseline or the baseline three injections followed by one injection of 225 mg at each week 4 and week 8. Up to 30% of patients could continue on a stable dose of one migraine-preventive medication. Of the 1,130 patients who were randomly assigned to fremanezumab quarterly (376), fremanezumab monthly (379), and placebo (375), 91-93% completed the trial. The mean change (± SE) in the average number of headache days per month within the 12-week intervention period compared to the baseline 28-day preintervention period was a decrease of 4.3 ± 0.3 days in the fremanezumab quarterly group, 4.6 ± 0.3 days in the fremanezumab-monthly group, and 2.5 ± 0.3 days in the placebo group (P < 0.001 for both comparisons with placebo). For the 12 weeks of the intervention, patients receiving placebo experienced an average of 10.4 ± 6.4 headache days compared to 8.5 ± 6.3 days for those receiving fremanezumab quarterly and 8.0 ± 6.3 days for those receiving fremanezumab monthly.

There was a significant reduction in the average number of migraine days per month and in the use of acute medication, as well as a significant increase in patients who demonstrated a reduction of at least 50% in the average number of headache days per month. Evidence of hepatic dysfunction, including elevation of liver enzyme levels to three or more times the upper limit of the normal range, occurred in three patients in the placebo group and five patients in each of the fremanezumab groups (P = 0.73 for each fremanezumab group vs. placebo, and P = 0.56 for the combined fremanezumab groups vs. placebo). The levels reverted to normal without discontinuation of the intervention.

The results described in the report by Goadsby et al are from the screening ( 3 weeks of initial screening and a four-week baseline phase) and the treatment phase with a subcutaneous injection of either erenumab, at a dose of 70 mg or 140 mg, or placebo monthly (24 weeks). Although the initial protocol did not permit patients to take a migraine-preventive medication, an amendment during the enrollment period allowed the concomitant use of one migraine-preventive medication. The mean number of migraine days per month at baseline was 8.3 in the overall episodic migraine population.

Of the 955 patients who underwent randomization (317 to the 70 g erenumab group, 319 to the 140 mg erenumab group, and 319 to the placebo group), 89.8% completed the six-month, double-blind treatment phase population. The primary endpoint of change from baseline to months four through six in the mean number of migraine days per month was reduced by 3.2 in the 70 mg erenumab group and by 3.7 in the 140 mg group, compared with a reduction of 1.8 days in the placebo group (P < 0.001 for each dose vs. placebo).

A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70 mg erenumab group and 50.0% of patients in the 140 mg group, compared with 26.6% in the placebo group (P < 0.001 for each dose vs. placebo). The number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70 mg erenumab group and by 1.6 days in the 140 mg group compared with a reduction of 0.2 days in the placebo group (P < 0.001 for each dose vs. placebo). There was significant improvement in physical impairment scores with treatment. There were no safety or trial completion differences between those treated and on placebo.

COMMENTARY

CGRP, an endogenous vasoactive neuropeptide, plays a key role in migraine pathophysiology, and has been studied as a treatment target for over a decade. CGRP receptors are found on first and second order trigeminal neurons and on smooth muscle cells in meningeal vessels. Levels of CGRP are increased in the blood of patients with a migraine, and injection of CGRP can induce a migraine-like headache.

Initially, CGRP antagonists were studied to provide acute migraine relief, and in 2008, a large Phase III trial demonstrated the benefit of an oral CGRP antagonist for acute abortive treatment; however, use of the specific oral antagonist to prevent episodic migraine was associated with significant liver toxicity.1

Now, researchers focus on blocking the CGRP molecule or receptor as a parenteral migraine preventive treatment. In 2014, published results of a trial of eptinezumab showed a significant decrease in migraine days after one infusion of the CGRP molecular antagonist.2 Further clinical trials are ongoing. The currently reviewed trials of subcutaneous treatment with monoclonal antibodies to either the CGRP molecule or its receptor found a mean reduction of about two migraine days a month compared to placebo treatment.

However, CGRP receptors are ubiquitous, and CGRP, in its alpha and beta forms, appears to modulate a wide variety of physiological functions in multiple major organ systems. Although the trajectory of research into CRGP antagonism is showing improving results, the long-term effects and benefits of potentially decades of this migraine-preventive treatment in a population that is predominantly women of childbearing age will take years to determine. The patients recruited into these clinical trials appeared to experience migraines refractory to usual preventive therapy. The mean benefit of the parenteral treatment, while significant, was not overwhelming and likely varies considerably over the wide range of migraineurs.

Each individual migraine sufferer, and her insurance company, will have to decide if intermittent subcutaneous injections of CGRP is a treatment to be initiated early in the stepwise trials of preventive therapy or is treatment to be tried when other proven therapies fail.

Like onabotulinum injections, cost probably will restrict insurance-covered use to those who have failed other therapies. Because so many individuals suffer from migraines, there will be a large population of potential therapeutic candidates, if CGRP antagonism becomes an approved preventive treatment in the near future.

REFERENCES

  1. Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment trial. Lancet 2008;372:2115-2123.
  2. Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100-1107.